APPLICANT'S ABSTRACT: The challenge for the new century lies in the detailed analysis of complex disease systems wherein multiple genes, as well as environmental influences, are responsible for the manifestation of a diverse set of symptoms that characterize the disease. The major obstacle in the study of complex diseases is to identify significant associations between genetic variants (genotypes) and symptoms or conditions of the disorder (phenotypes). Using recently developed methods of linkage analysis, the proposed study will determine phenotypically significant polymorphisms involved in alcoholism and alcohol-related disorders. Genetic variants will be assayed in DNA extracts that have associated, clinical diagnoses of alcohol dependence, related physiological responses, and psychiatric conditions. Detailed haplotypes based on these genetic variants will then be constructed and tested for association with the clinical diagnoses utilizing linkage analysis and nested cladistic analysis methods. The resulting data will have both practical and theoretical applications. Novel variants involved in alcoholism and alcohol-related disorders will be identified. Of broader impact, the proposed study will be used as a model system for the investigation of any complex disease. The identification of significant genotype:phenotype associations is the key to understanding the etiology of complex disease systems and to developing improved methods of prevention and treatment.